Patients infected with hepatitis C virus (HCV) and their physicians have long been awaiting a more tolerable and effective treatment regimen. New agents are currently in development that directly target the HCV life cycle [direct-acting antivirals (DAAs)]. This review discusses these agents and the targets of therapy.

Figure 1. Viral life cycle. HCV enters the cell by receptor-mediated endocytosis. Positive-strand RNA is released into the cytoplasm, and then it is translated into a polyprotein. Polyprotein processing occurs: the bonds between the proteins are cleaved, and this results in four structural proteins and six nonstructural proteins. Viral replication occurs through the creation of negative-strand RNA, which serves as a template for the production of positive-strand RNA; that RNA is then packaged and released from the cell.

(Click table to enlarge)

NS3/4A

NS3/4A protease inhibitors (PIs) are the furthest along in drug development and include telaprevir and boceprevir, which have been approved for clinical use. NS3/4A PIs have high antiviral efficacy against genotypes 1 and 2 but not against genotype 3.2

NS3/4A inhibitors have a low genetic barrier to resistance; resistant strains develop quickly and prevent viral eradication with monotherapy.3, 4 HCV subtype 1a develops resistant strains to telaprevir more quickly than subtype 1b. One nucleotide change is required for subtype 1a to change the amino acid and form a resistant strain, whereas two nucleotide changes are required for subtype 1b (Fig. 2).5

Figure 2. Telaprevir resistance. One common location for the development of strains resistant to telaprevir is position 155. In patients with genotype 1a, the nucleotide sequence is AGA, which codes for arginine. Only one nucleotide change is required to result in the AAA sequence, which codes for lysine. This is in contrast to genotype 1b: two nucleotide changes are required for the AAA sequence and the change to lysine.

NS5B

Two categories of NS5B RNA polymerase inhibitors are in development: nucleoside inhibitors (NIs) and nonnucleoside inhibitors (NNIs). NIs mimic the natural substrates, are incorporated into the growing RNA chain, and cause termination of replication.6 NNIs bind to distant sites on the enzyme and cause a conformational change, which renders the polymerase ineffective.6, 7

There is a high genetic barrier to resistance with polymerase inhibitors and particularly with NIs because the active site of NS5B is highly conserved and amino acid substitutions at every position of the active site can result in a loss of function.8 Because NNIs bind to sites distant from the active center, resistance develops more frequently. Similarly, NIs have antiviral activity against all HCV genotypes because the active site of NS5B is conserved; however, NNIs have a more limited spectrum of activity.9

Other

The NS5A viral protein and cyclophilin A host protein are also important components of the viral replication complex (Fig. 3), and agents that target these proteins, which have been termed replicase-binding inhibitors, are also in development.3 The exact mechanism by which these proteins participate in viral replication is currently under investigation, although early trials with inhibitors of these proteins have shown robust antiviral activity.10, 11

Figure 3.Replication complex. The viral nonstructural proteins, in addition to host proteins such as cyclophilin A, make up the replication complex and are the targets of the new DAA therapy. The exact roles of many of these proteins are still being elucidated, although inhibitors directed at them have potent antiviral activity.

Current Practice and Future Directions

At the present time, because of the relatively high efficacy of treatment, patients infected with genotypes 2 and 3 receive 24 weeks of treatment with pegylated interferon-α (PEG-IFNα)/ribavirin (RBV).12 However, the side effects and the duration of treatment remain limitations, and DAAs are in development that will treat patients infected with genotypes 2 and 3.

The standard-of-care treatment for patients with genotype 1 infections now includes the use of telaprevir or boceprevir in combination with PEG-IFNα/RBV. Overall, the additions of telaprevir and boceprevir have improved the rates of response, but the significant side effects and the duration of treatment remain problems.13–17 Additionally, there are certain subgroups of patients who do not benefit from the addition of telaprevir or boceprevir to PEG-IFNα/RBV. Tables 2 and 3 and Fig. 4 show the results of phase 3 trials and highlight those groups that continue to have suboptimal response rates with triple therapy.13–17

Figure 4.SVR rates according to the fibrosis score in the REALIZE study. SVR indicates a negative viral load 24 weeks after the completion of therapy. The REALIZE study evaluated the efficacy of telaprevir in prior treatment relapsers, partial responders, and null responders. The results came from subgroup analyses.

† In the ADVANCE trial of telaprevir,13 the T12PR group received telaprevir plus PR for 12 weeks and then PR alone for 12 weeks if HCV RNA results were negative at weeks 4 and 12 or for 36 weeks if HCV RNA was detectable at either time point. The T8PR group received telaprevir plus PR for 8 weeks, then a placebo plus PR for 4 weeks, and finally PR for 12 or 36 weeks (depending on the HCV RNA levels at weeks 4 and 12).

‡ In the ILLUMINATE trial of telaprevir,15 all patients received 12 weeks of telaprevir plus PR. The HCV RNA level was assessed at weeks 4 and 12. If HCV RNA results were negative at weeks 4 and 12, patients were randomized into two groups: the T12PR24 group, which received another 4 weeks of therapy, and the T12PR48 group, which received another 28 weeks of therapy. Patients who did not achieve negative HCV RNA results at weeks 4 and 12 received 28 additional weeks of PR (i.e., the T12PR48 RGT group).

§ In the SPRINT-2 trial of boceprevir,16 the RGT group received PR for 4 weeks and then boceprevir for 24 weeks plus PR for 28 weeks. If patients had negative HCV RNA results at weeks 8 and 24, they stopped therapy at 28 weeks; if patients had detectable HCV RNA, they continued for another 20 weeks. The BPR48 group received lead-in PR for 4 weeks and then boceprevir plus PR for 44 weeks.

† In the REALIZE trial of telaprevir,14 the T12PR48 group received telaprevir plus PR for 12 weeks and then PR for 36 weeks. The Li-T12PR48 group received PR for 4 weeks, then telaprevir plus PR for 12 weeks, and finally PR for 32 weeks.

‡ In the RESPOND-2 trial of boceprevir,17 the RGT group received PR for 4 weeks and then boceprevir plus PR for 32 weeks. Patients with negative HCV RNA results at weeks 8 and 20 stopped treatment at week 36; patients with detectable HCV RNA received therapy for another 12 weeks. The BPR48 group received lead-in PR for 4 weeks and then boceprevir plus PR for 44 weeks.

§ Not studied.

Generally, interferon-α is the drug that limits tolerability in the majority of patients. Thus, future regimens are being developed first to minimize interferon-α exposure and then ideally to avoid it entirely. Phase 3 trials of PIs have demonstrated that patients who achieve an extended rapid virological response can receive a shortened course of therapy (24 weeks with telaprevir and 28 weeks with boceprevir) with similar overall response rates. Thus, PIs may be considered the first interferon-α–sparing therapy.

The use of multiple DAAs is currently being studied with the goal of developing interferon-α–sparing and interferon-α–free regimens. Figure 5 shows the various combinations of therapy that are currently being studied both with and without PEG-IFNα and RBV.18 Over the next 5 to 10 years, as we work to develop an effective interferon-free regimen, there will be ongoing research to determine the shortest duration of interferon-α–sparing therapy possible. Quadruple-therapy regimens are likely the next step in this process.

Figure 5.Combinations of DAAs currently under study. Trials are being conducted that include regimens of quadruple therapy (2 DAAs plus PEG-IFNα/RBV) as well as regimens using RBV but not PEG-IFNα and regimens using only DAAs.

Evidence showing that a sustained virological response (SVR) can be achieved with the use of DAAs and without the concurrent use of PEG-IFNα and RBV has been published recently.19 Patients with genotype 1 and a prior treatment null response were treated with an NS5A replication complex inhibitor (Daclatasvir) and an NS3 PI (Asunaprevir) alone or in combination with PEG-IFNα/RBV. All patients who received the quadruple therapy achieved SVR by 12 weeks, and 4 of 11 patients who received the all-oral regimen achieved SVR by 12 weeks. These results provide proof of concept that quadruple therapy offers hope of cure to previous null responders and that treatment regimens that do not include interferon-α are possible and likely. Many of the treatment regimens under investigation still include RBV; this is due to evidence from phase two studies of PIs showing that the use of RBV decreases viral breakthrough and relapse.20

Many of the treatment regimens under investigation still include RBV; this is due to evidence from phase two studies of PIs showing that the use of RBV decreases viral breakthrough and relapse.20

Personalized Treatment Regimens

HCV is leading the field of personalized medicine. Depending on a patient's history of treatment, degree of fibrosis, and race, a potential future treatment strategy involves the separation of patients into those with a favorable response profile and those with an unfavorable response profile and then the choice of an appropriate treatment regimen. Patients who have a favorable response profile will more frequently respond to the triple-therapy regimens that are currently available and may be the ones who will do well with the early interferon-free regimens. Patients who have an unfavorable response profile may experience improved response rates with upcoming quadruple therapy while additional interferon-α–sparing and interferon-α–free regimens are in development. Another potential future treatment algorithm may include the upfront treatment of patients with combination DAA therapy and, if the treatment fails, the initiation of a regimen that also includes PEG-IFNα/RBV (Fig. 6).

Figure 6. Potential future treatment strategies.

In conclusion, the development of new antiviral agents is currently underway with the ultimate goal of using DAAs to target multiple viral and host proteins to increase antiviral efficacy, prevent resistance, and improve the side effect profile of HCV treatment.

Received 8 August 2011; received in revised form 2 November 2011; accepted 17 November 2011. published online 14 December 2011.

Abstract

Background & Aims

This study aimed at developing a predictive algorithm based on interleukin 28B (IL28B) genotype, hepatitis C virus (HCV) genotype, and plasma HCV-RNA load, which could accurately allow us to define the probability of response to pegylated interferon (Peg-IFN) plus ribavirin (RBV) therapy in HIV/HCV-coinfected patients.

Methods

Five hundred and twenty-one treatment-naive HIV-infected patients, who initiated HCV therapy with Peg-IFN/RBV, were analysed in an on-treatment basis. Patients were categorized as unlikely responders, uncertain responders, and anticipated responders (<20%, 20–60%, and >60% probability to achieve SVR, respectively).

Results

HCV genotype, baseline HCV-RNA load, and IL28B genotype were confirmed as independent predictors of SVR in a logistic regression analysis. A stepwise algorithm based on these three variables was created based on 321 patients and evaluated in the remaining 200 patients. Unlikely responders included patients with genotype 1 or 4, HCV-RNA load greater than or equal to 600,000 IU/ml, and rs12979860 non-CC (rate of SVR: 17.3%). Anticipated responders were those with HCV genotype 2–3, patients harboring HCV genotype 4 and IL28B CC, as well as those who simultaneously bore HCV genotype 1, HCV-RNA load <600,000 IU/ml, and IL28B CC (rate of SVR 74.1%, 77.8%, and 64.4%, respectively). The area under the receiver operating characteristic curve of the model was 0.77 (0.733–0.814).

Conclusions

The combined use of IL28B genotype, HCV genotype, and HCV-RNA load enables to easily identify patients with a high and very low likelihood of SVR. HCV therapy could be deferred in the latter patients, until more effective options are available, at least if they do not show advanced liver fibrosis.

The Bloomberg administration is launching a campaign to prevent the spread of the deadly hepatitis C virus, The Post has learned.

The Check Hep C initiative targets high-risk populations in Harlem, the South Bronx, central Brooklyn and parts of Staten Island and Queens.

At-risk populations include drug users who have shared infected needles, people infected with HIV and immigrants from countries with high hepatitis prevalence, including Egypt, Pakistan and the former Soviet Union.

Hepatitis C, when undetected, can cause fatal liver disease.

The city Health Department will award up to $1.3 million in contracts to community-based medical clinics that would provide free counseling and hepatitis C testing.

Patients will also be given a “health coach” to help navigate the medical system. And there will be a community-awareness campaign to reach those at risk.

The Fund for Public Health, the fund-raising arm of the Health Department, is providing financing for the project.

While no systemic treatment currently exists for liver cancer (hepatocellular carcinoma), a series of experiments in rats has identified viable target worthy of further investigation.

A gene called LSF (Late SV40 Factor) may be a target in liver cancer that drugs could be developed to target and wipe out.

Every cancer has a series of common mutations that predispose the transformation from normal cell to cancer. These genes are called oncogenes. Some cancers have a unique profile with specific oncogenes for that cancer, or may share similar mutations with other, closely related cancers.

In the search for a systemic treatment for liver cancer, the LSF gene has been shown in previous studies to appear specifically in hepatocellular carcinoma.

LSF, like many oncogenes, regulates cellular growth. After completing their laboratory experiments and transplating human cancers into rats, researchers concluded that LSF inhibition is worthy of further study and remains a promising drug target.

Boston University researchers began testing 20 compounds of isoquinolinones, with one candidate quickly outperforming the others.

Factor Quinolinone Inhibitor 1 (FQI1) is the lead candidate for further study, and was proven to inhibit DNA replication of LSF in studies performed both in a laboratory setting and inside the cell.

Most notably, FQI1 increased cellular death in cancer, but did not affect normal cells.

Supplementary information provided by the publication of the study extensively documents the methods used by the team to make the isoquinolinones compounds referenced.

Research was published in the journal Proceedings of the National Academy of Sciences of the United States of America.

The authors of the study declared that there was no financial conflict of interest in the publication of their research.

Liver Cancer (Hepatocellular Carcinoma)

The American Cancer Society estimates that there are over 26,000 new cases of primary liver cancer and bile duct cancer in the United States each year, and they are responsible for over 19,000 deaths. The average man has about a 1% chance of developing this cancer over his lifetime, while the average woman has about a half percent chance.

Primary liver cancer most commonly includes hepatocellular carcinoma (HCC) and can coexist with cholangiocarcinoma, a cancer of the bile ducts between the liver and gall bladder. It is important to note that most cases of cancer in the liver are metastases from other cancers, such as those from the colon, breast, or prostate. Primary liver cancers begin in the liver itself. Other less common forms of primary liver cancer include angiosarcomas and hemangiosarcomas (cancers that begin in the blood vessels of the liver), lymphoma of the liver, and hepatoblastoma (a rare pediatric cancer usually occurring in children under three years of age). There are also several variants of benign liver tumors. Hepatocellular adenomas (a benign liver tumor associated with oral contraceptive use and glycogen storage disease) must be watched closely, as they have a potential to turn cancerous.

Hepatocellular carcinoma, the most common form of liver cancer, is strongly associated with infection by chronic hepatitis B and C. These infections cause liver cancer more often in Asian and African countries where hepatitis viruses are endemic and people acquire the disease early in their life.

Cases of liver cancer in the United States have tripled over the past three decades. While the most common cause of liver cancer used to be from alcohol abuse and the resulting cirrhosis of the liver, hepatitis C infection is now a leading cause. Obesity, particularly fatty liver disease, is also implicated. Other causes include hemochromatosis (a disease that causes the body to store too much iron), high exposure to aflatoxins (a mold found in peanuts, rice, soybeans and corn; rare in developed countries), and Type 2 diabetes.

Symptoms of HCC usually present with classic signs of liver dysfunction such as jaundice (yellowing of the skin due to too much bilirubin), bruising and blood clotting problems (due to the liver making the clotting factors in our blood), and ascites (fluid buildup in the abdomen from liver dysfunction). Other general symptoms include nausea, fatigue, vomiting, and unintentional weight loss.

In patients who are at high risk for HCC, screening is usually done with ultrasound and CT scan, as well as MRI. While there is no reliable blood test for liver cancer screening, a high level of alpha-fetoprotein (AFP) should be considered suspicious for liver cancer. Liver biopsy is also done, although this is not necessary for diagnosis if imaging is definitive.

Treatment for HCC is difficult, as many patients with liver cancer also have damaged livers from cirrhosis. Treatment must be balanced between treating the cancer and also mitigating the risk of liver failure. Early stage cancer has the potential for surgical removal, however most cases of liver cancer are discovered when they are advanced, making surgery difficult. Other treatments are dependent on the size and location of the tumors, such as ethanol injection into the tumor (small tumors), radiofrequency ablation (using high-frequency radiowaves to destroy the tumor), transcatheter arterial chemoembolization (cuts off the blood supply to unresectable tumors), and cryosurgery (destroying cancerous tissue with subzero temperatures). Liver transplantation is a relatively successful option for patients without metastatic spread. Sorafenib (marketed as Nexavar) is a tyrosine kinase inhibitor that has shown efficacy in treating HCC.

Ultimately, HCC is a difficult cancer to treat and survival rates are low, with most cancers being unable to be completely removed. These patients usually succumb to the disease within three to six months. Across the board, patients with a solitary small tumor of less than three centimeters in size have a five-year survival rate of 20%. Patients with advanced disease have a one-year survival rate of 30%.

Prevention of liver cancer is extremely effective if vaccinated against hepatitis B. Avoidance of alcohol abuse is also effective. Other patients with different causes of cirrhosis or chronic liver inflammation will benefit from routine ultrasound screening and AFP measurements in the hope of detecting cancer early.

Hepatitis C is a form of chronic liver disease that results in 8,000 to 10,000 deaths in the United States each year. People suffering complications from hepatitis C can develop jaundice, internal bleeding, malnutrition, and kidney damage. Hepatitis C is the leading cause of liver failure, for which the only viable treatment is liver transplantation.

Until recently, the standard treatment for hepatitis C has been only somewhat successful, curing just under 50 percent of patients. However, in 2011 the Food and Drug Administration approved two new drugs, Victrelis and Incivek. When used in conjunction with the standard treatment, these new medications have increased the cure rate for hepatitis C to about 70 percent. In addition, there are newer drugs currently being studied that appear to offer even higher levels of cure with fewer side effects. We expect these medications to be available in about three years.

» What if I was treated for hepatitis C before and I was not cured? Following FDA approval of Victrelis and Incivek, my colleagues and I called our patients with hepatitis C who were not cured after following the standard therapy and invited them to come back in for the new treatment. We've had very good success, our patients have responded well, and our cure rate reflects the national cure rate of approximately 70 percent.

» What is the new treatment protocol? The treatment protocol for hepatitis C lasts for 24 to 48 weeks and it can have some unpleasant side effects, including fatigue, skin rash, and low white-blood-cell count. The protocol requires a weekly shot of interferon and daily pills to enhance the impact of the interferon. One of the new medications is added to this standard treatment regimen and while it may increase the side effects, it can also shorten the duration of treatment.

» How do you know the treatment has been successful? As treatment progresses, we measure the virus counts by drawing blood samples. Prior to treatment, it is not unusual for the virus count of someone with hepatitis C to measure in the millions. Our goal is for the virus count to become undetectable within a few weeks of treatment and with these new drugs we are able to accomplish this in the majority of patients. It is very gratifying to see a patient's virus count go from 10 to 20 million to virtually nothing.

» What if I have already suffered liver damage from hepatitis C? Studies have shown that if patients with liver damage undergo successful therapy for hepatitis C and the virus is eliminated, the liver can partially recover from the damage. This is an important incentive for people who have undergone the standard treatment for hepatitis C with no success.

» How do people contract hepatitis C? Hepatitis C is only acquired by blood-to-blood contact. This can happen by sharing a syringe or sharing a razor blade. Nurses and doctors are at increased risk because they can get accidentally stuck with a needle while treating a patient. Rescue personnel at the scene of a bloody accident are also at higher risk if they suffer a cut in the line of duty. Blood transfusions were not screened for hepatitis C until the 1980s, so people who received transfusions prior to that time are at higher risk.

There is a widespread misconception that once you have hepatitis C there is no cure, but this is not true. The new treatment is very promising. If you have been treated for hepatitis C in the past with no success, I urge you to try again for a cure with the new drugs now available.

Dr. Carl West is board certified in gastroenterology and internal medicine. He is on the medical staff of Cayuga Medical Center and is in practice with Gastroenterology Associates of Ithaca, where he can be reached at (607) 272-5011.

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